KR100378255B1 - Stereoselective preparation method of β-D-mannopyranoside - Google Patents

Abstract

The present invention provides a method for synthesizing β-D-mannopyranoside stereoselectively by reacting a lanthanide catalyst with a compound represented by the following formula (1) and a lower alcohol, monosaccharide or polysaccharide.

Wherein R ₁ represents hydrogen, a lower alkyl group of C ₁ to C ₆ or a phenyl derivative; R ₂ represents a hydrogen, alkyloxo, alkyloxyacetyl or alkyloxoacetyl group, wherein alkyl means C ₁ to C ₆ lower alkyl; R ₃ , R ₄ and R ₅ independently of one another represent a protecting group of hydrogen or a hydroxy group; n represents the integer of 0, 1, or 2.

The production method according to the present invention has the advantage that the β-stereoselectivity can be increased by a relatively simple operation by using a lanthanide catalyst.

Description

Stereoselective preparation method of β-D-mannopyranoside {Stereoselective preparation method of β-D-mannopyranoside}

The present invention relates to a novel method for preparing β-D-mannopyronoside, and more particularly, to a method for stereoselectively synthesizing β-D-mannopyranoside using a lanthanide catalyst. will be.

Recently, it is known that carbohydrates are involved in various physiological processes in vivo, and many efforts have been made to understand the properties and roles of carbohydrates. Carbohydrates in cells are present in the form of glycoproteins or glycolipids and are known to play an important role in cell growth, immune responses, inflammation, and viral infections. In particular, glycoproteins essentially contain residues of β-D-mannopyranosides. However, chemical synthesis of biologically important oligosaccharides, particularly stereoselectively synthesizing β-D-mannopyranosides, is known to be very difficult.

As a method for synthesizing stereoselective β-D-mannopyranoside known to the literature so far, first, the method using intramolecular aglycon delivery (IAD) ( J. Am. Chem. Soc. 1991 , 113 , 9376; J. Am . Chem. Soc. 1996 , 118 , 247; Angew. Chem. Int. Ed. Engl . 1994, 33, 1765). To synthesize β-forms ( J. Org. Chem. 1997 , 62, 1198).

However, the method using the IAD requires covalent linking of sugar-coated to sugar-coated sugars through a suitable linking branch, which requires several steps and uses a rather unstable intermediate. In addition, the yield is generally low when the sugar acceptor is secondary alcohol. Secondly, in the method of adding sugar acceptor, the selectivity was lowered in the secondary alcohol and the desired result was not obtained except some sugar crab.

Accordingly, the technical problem to be achieved by the present invention is to provide an effective method for preparing β-D-mannopyranoside as an IAD strategy through a non-covalent bond that solves the above problems.

In order to achieve the above technical problem, the present invention is to produce a compound represented by the following formula (4) by reacting the compound represented by the formula (1) and the compound represented by the formula (2) in the presence of an additive represented by the formula (3).

[Formula 1]

Wherein R ₁ represents hydrogen, a lower alkyl group of C ₁ to C ₆ or a phenyl derivative; R ₂ represents a hydrogen, alkyloxo, alkyloxyacetyl or alkyloxoacetyl group, wherein alkyl means C ₁ to C ₆ lower alkyl; R ₃ , R ₄ and R ₅ independently of one another represent a protecting group of hydrogen or a hydroxy group; n represents the integer of 0, 1, or 2.

ROH

Wherein R represents C ₁ to C ₆ lower alcohols, monosaccharides or polysaccharides.

Ln _ℓ X _m

Ln is a lanthanide element; X is a halogen element such as F, Cl, Br or I, trifluoromethanesulfonate (OTf), hydroxy (OH), nitro (NO ₃ ), oxygen (O), acetoxy (CH ₃ CO ₂ ), Ligands such as sulfonate (SO ₄ ); l is an integer of 1 or 2; m represents the integer of 2, 3, or 4.

In which R ₁ represents hydrogen, a lower alkyl group of C ₁ to C ₆ or a phenyl derivative; R ₂ represents a hydrogen, alkyloxo, alkyloxyacetyl or alkyloxoacetyl group, wherein alkyl means C ₁ to C ₆ lower alkyl; R ₃ and R ₄ independently of each other represent a protecting group of hydrogen or a hydroxy group; R is as defined in the formula (2).

Unless otherwise specified in the present invention, each term refers to the following meaning.

The term "protecting group of hydrogen or hydroxy" is, for example, methoxymethyl, methoxythiomethyl, triethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, triethylsilyl, triphenyl Silyl, benzyl, p-methoxybenzyl, t-butoxymethyl, tetrahydropyranyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, diphenylmethyl and triphenylmethyl and the like.

"Lower alkyl" means straight or branched alkyl having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and phenyl.

The term "lower alcohol" means an alcohol substituted with the lower alkyl, and examples thereof include methanol, ethanol, propanol, isopropanol, butanol and phenol.

The "lanthanide element" is an element having atomic numbers 57 to 71, and preferably Yb, La Sm, Eu, and the like.

Hereinafter, the preparation method according to the present invention will be described in detail through a reaction scheme. In the following scheme, R ₁ , R ₂ , R ₃ , R _4, R _5, R, Ln, X, L, m and n are as defined above. The production method of the present invention for achieving the above technical problem can be described by the following scheme.

Scheme 1

First, in the above reaction scheme, the lanthanide catalyst represented by the formula (3) is added to the compound represented by the formula (1) and the formula (2), which can be prepared by conventional methods well known in the art, to stereo-selectively β-D- Mannopyranosides are prepared. Hexane, benzene, toluene, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, diethyl ether, dichloromethane, chloroform, acetonitrile and the like are used as the solvent of the above reaction scheme.

In addition, N-bromosuccinimide (NBS), N-urethosuccinimide (NIS), N-chlorosuccinimide (NCS), trifluoromethanesulfonic acid (TfOH), trifluoro Any one or more catalysts selected from the group consisting of romethanesulfonic anhydride (Tf ₂ O) and the like may be further added. In addition, the reaction scheme may be made at -100 to 50 ^o C, preferably at -80 to 30 ^o C.

Through the following examples will be described the present invention in detail. The scope of the present invention is not limited by the following examples.

Example 1

Preparation of Methyl 2,3,4-tri-O-benzyl-6-O- (3,4,6-tri-O-benzyl-D-mannopyranosyl) -α-D-glucopyranoside

3,4,6-Tri-O-benzyl-1-ethylsulfinyl-D-mannopyranoside (30 mg, 60 μmol) and methyl 2,3,4-tri-O-benzyl-α under argon gas conditions -D-glucopyranoside (33.4 mg, 72 μmol) was dissolved in acetonitrile (1 ml). Eu (OTf) ₃ (36 mg, 60 μmol) and molecular sieves (100 mg) were added and stirred at −40 ^° C. for 1 hour, followed by quenching with saturated sodium thiosulfate (0.5 ml). The inorganic material was removed using Celite, the organic layer was extracted with dichloromethane and washed with saturated NaHCO ₃ , saturated sodium thiosulfate and brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then methyl 3,4-tri-O-benzyl-6-O- (3,4,6-tri-O-benzyl-D-mannopyranosyl by fast column chromatography. ) -α-D-glucopyranoside was obtained in 82% yield. This compound obtained α and β in a ratio of 1: 4.3. Observed stereoselectivity corresponds to a 17.2-fold increase in the production of β-anomers compared to when no Eu (OTf) ₃ additive was used.

α-anomer

Rf: 0.17 (hexane: ethyl acetate = 2: 1)

[α] _D ²⁵ = +71.2 (c = 0.95, CH ₂ Cl ₂ )

¹ H NMR (CDCl ₃ ):

δ 7.40-7.10 (m, 30H, aromatic), 5.02-4.40 (m, 12H, 60 CH ₂ Ph), 4.96 (d, J = 1.5, 1H, H-1 ′), 4.60 (d, J = 3.7, 1H, H-1), 4.03 (dd, J = 3, 15, 1H, H-2 '), 3.99 (app t, J = 9.4, 1H, H-3), 3.85 (dd, J = 4.5, 10.0 , 1H, H-6a), 3.83 (m, 1H, H-3 '), 3.82 (dd, J = 3.5, 10.0, 1H, H-6b), 3.70 (m, 3H, H-5, H-4 ', H-5'), 3.62 (dd, J = 4.0, 11.0, 1H, H-6a '), 3.55 (dd, J = 2.0, 11.0, 1H, H-6b'), 3.50 (dd, J = 3.7, 9.8, H-2), 3.45 (app t, J = 9.4, 1H, H-4), 3.33 (s, 3H, OMe), 2.40 (br s, O H )

¹³ C NMR (CDCl ₃ ):

δ 138.8-137.8, 128.5-127.5 (aromatic), 99.5, 97.8, 82.1, 80.0, 79.9, 77.7, 74.2, 71.2, 69.8, 68.2, 75.8, 75.0, 74.9, 73.4, 73.2, 71.9, 69.8, 65.9, 55.1 O Me )

β-anomer

Rf: 0.20 (hexane: ethyl acetate = 2: 1)

[α] _D ²⁵ = +34.82 (c = 0.35, CH ₂ Cl ₂ )

¹ H NMR (CDCl ₃ ):

δ 7.35-7.15 (m, 30H, aromatic), 5.0-4.53 (m, 12H, 60 CH ₂ Ph), 4.51 (d, J = 3.5, 1H, H-1), 4.10 (app s, 1H, H- 1 '), 4.09 (dd, J = 1.5, 10.8, 1H, H-6a'), 4.00 (2t, 1H, J = 9.5, H-3, H-4 '), 3.91 (br s, 1H, H -2 '), 3.82 (t, J = 9.5, 1H, H-4), 3.76 (m, 1H, H-5'), 3.73 (dd, J = 2.0, 10.2, 1H, H-6a), 3.66 (dd, J = 5.0, 10.2, 1H, H-6b), 3.56 (dd, J = 5.5, 10.8, H-6b ') 3.50 (m, 2H, H-2, H-3'), 3.32 (m , 1H, H-5), 3.32 (s, 3H, OMe), 2.37 (br s, 1H, OH) ppm

¹³ C NMR (CDCl ₃ ):

δ 138.8-138.0, 128.5-127.6 (aromatic), 100.0, 97.9, 82.2, 81.3, 79.9, 77.6, 75.4, 74.3, 69.8, 68.3, 75.7, 75.2, 74.7, 73.5, 73.4, 71.4, 69.3, 68.18, 55.20 ( O Me )

Example 2

Preparation of Methyl 3,4,6-tri-O-benzyl-β-D-mannopyranoside

Phenyl 2-O- (acetoxyacetyl) -3,4,6-tri-O-benzyl-1-thio-D-mannopyranoside (30 mg, 4.8 μmol) under argon gas conditions was diluted with acetonitrile (1 ml). Melted). Yb (OTf) ₃ (10.3 mg, 19.2 μmol) and molecular sieve (100 mg) were added and stirred for 1 hour, followed by addition of N-bromosuccinimide (1.7 mg, 9.6 μmol). And sugar acceptor methanol (185 µL, 4.8 µmol) was slowly added dropwise at room temperature over about 1 hour. After further stirring at room temperature for 3 hours, the reaction was stopped with saturated sodium thiosulfate (0.5 ml). The inorganic material was removed by filtration through celite, the organic layer was extracted with dichloromethane, and washed with saturated NaHCO ₃ , saturated sodium thiosulfate and brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and methyl 3,4,6-tri-O-benzyl-mannopyranoside was obtained by flash column chromatography in a yield of 57%. In this case, only β-anomer was selectively obtained, and when the Yb (OTf) ₃ additive was not used, only the α-anomer was produced.

Rf: 0.38 (hexane: ethyl acetate = 1: 1)

[α] _D ²⁵ = -13.0 (c = 0.35, CHCl ₃ )

¹ H NMR (CDCl ₃ ):

δ 7.35-7.18 (m, 15H, 3OCH ₂ Ph ), 4.90-4.52 (m, 6H, 3O CH ₂ Ph), 4.33 (d, J = 0.8, 1H, H-1), 4.08 (app s, 1H, H-2), 3.86 (t, J-9.3, 1H, H-4), 3.78 (dd, J = 2.3, 10.7, 1H, H-6a), 3.72 (dd, J = 5.0, 8.4, 1H, H -6b), 3.58 (app t, J = 3.5, 1H, H-3), 3.55 (s, 3H, O Me ) 3.45 (m, 1H, H-5), 2.40 (br s, 1H, O H )

¹³ C NMR (CDCl ₃ ):

δ 138.1, 128.4-127.5 (aromatic), 100.7, 81.5, 75.2, 75.1, 74.2, 73.5, 71.4, 69.2, 68.1 (3O C H ₂ Ph, ring carbon), 56.9 (O Me )

Although the present invention has been described with reference to the embodiments, these are merely exemplary, and it will be apparent to those skilled in the art that various changes and equivalents can be made therefrom. Therefore, the true technical protection scope of the present invention will be defined by the technical spirit of the appended claims.

As described above, the method for preparing β-D-mannopyranoside according to the present invention is simple and steric, by using a lanthanide catalyst, without the need for synthesizing sugar starting materials required by a known method through several steps. There is an advantage that it is possible to manufacture the β- form selectively.

Claims (5)

A method for preparing a compound represented by Formula 4 by reacting the compound represented by Formula 1 with the compound represented by Formula 2 in the presence of an additive represented by Formula 3. [Formula 1] [Formula 2] ROH [Formula 3] Ln _ℓ X _m [Formula 4] In the above formulas, R ₁ represents hydrogen, C ₁ to C ₆ lower alkyl group or phenyl derivative; R ₂ represents a hydrogen, alkyloxo, alkyloxyacetyl or alkyloxoacetyl group, wherein alkyl means C ₁ to C ₆ lower alkyl; R ₃ , R ₄ and R ₅ independently of one another represent a protecting group of hydrogen or a hydroxy group; ROH represents C ₁ to C ₆ lower alcohols, monosaccharides or polysaccharides; Ln represents a lanthanide element; X is a ligand such as a halogen element, trifluoromethanesulfonate (OTf), hydroxy (OH), nitro (NO ₃ ), oxygen (O), acetoxy (CH ₃ CO ₂ ), sulfonate (SO ₄ ) Represents; l is an integer of 1 or 2; m is an integer of 2, 3, or 4; n represents the integer of 0, 1, or 2. The compound of formula 1, wherein the compound of formula 4 is 2,3,4-tri-O-benzyl-6-O- (3,4,6-tri-O-benzyl-D-mannopyranosyl) D-glucopyranoside production method. The method of claim 1, wherein the compound of formula 4 is methyl 3,4,6-tri-O-benzyl-β-D-mannopyranoside. The method according to claim 1, wherein N-bromosuccinimide (NBS), N-urisuccinimide (NIS), N-chlorosuccinimide (NCS), triflic acid ( TfOH), triflic acid anhydride (Tf ₂ O) and the like, any one or more selected from the group consisting of. The solvent according to claim 1, wherein at least one selected from the group consisting of hexane, benzene, toluene, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, diethyl ether, dichloromethane, chloroform and acetonitrile is used as a solvent. Manufacturing method characterized in that.